A. Field of the Invention
The invention generally relates to a therapeutic composition of matter and method for administering said composition to human beings. Particularly, the several embodiments of the invention provide for treatment of renal disorders, such as uremia for alleviating the effects of tissue wasting disorders characterized by protein deficiency and for altering metabolic pathways in order to prevent leakage of nitrogen from the body's metabolic pool.
B. Description of the Prior Art
Prior art treatment of the several bodily disorders to which the present invention finds application varies according to the particular disorder, this variation resulting in certain instances from a lack of understanding of the metabolic processes involved in the respective situations. Other than dialysis, prior art treatments applicable to renal disorders, such as uremia, center around replacement of amino acids lacking in the individual suffering from said disorder. In a situation of this nature, nitrogenous wastes resulting from the normal breakdown of amino acids in the body are not adequately excreted and accumulate in the blood. Due to the inability to excrete these wastes, ingestion of protein must be restricted, thereby resulting in amino acid deficiencies. One particular treatment disclosed by Howe et al. in U.S. Pat. No. 2,457,820 provides for administering certain essential amino acids to correct this protein deficiency without overburdening the remaining kidney function.
Bergstrom et al. in U.S. Pat. No. 3,764,703 discloses a mixture of eight essential amino acids optionally combined with either or both L-arginine and L-histidine (which the patent calls "semi-essential" amino acids) for treatment of uremic conditions caused by renal insufficiency. However, the provision of additional amino acids in the blood stream often results in overburdenment of the kidney function, especially in severe cases, due to the resulting breakdown of the introduced amino acids into excessive nitrogenous wastes. Furthermore, these compounds are highly unpleasant to taste. For a comparison of results of essential amino acids therapy as opposed to that employing essentially the compositions of the present invention, see Walser et al. (1973), Journal of Clinical Investigation, 52:679. Also, Walser, M., (1975) "Keto-acids in the Treatment of Uremia", Clinical Nephrology, 3:80.
Other workers studying renal failure have suggested the dietary use of keto-acid analogs of amino acids and have proposed but have not demonstrated the use of keto-analogs of a combination of certain essential amino acids as a therapeutically beneficial treatment for uremia. These prior suggestions have been based on the assumption that such keto-acid analogs might combine with nitrogen derived from urea breakdown in the intestines. Subsequently, such suggestions relating to keto-acid usage have been discounted. See editorial in The Lancet, Aug. 2, 1975, page 214. The work resulting in the present invention has demonstrated the actual therapeutic value of keto-acid usage and has proven the prior assumptions to be inaccurate. In particular, urea breakdown in renal disorders does not produce an excess of nitrogen in the body. To the contrary, the amount of urea breakdown in the body in renal failure is normal. Thus, an excess of nitrogen is not available to aminate keto-acids and, even if urea breakdown is reduced to zero, the therapeutic use of keto-acids proves effective. The present teachings are thus based on heretofore unobvious understandings of the body's metabolic processes. Nitrogen is diverted away from urea formation, this nitrogen now being known to derive from body metabolic processes themselves. A particular object of the invention can then be seen to be the suppression of urea formation. Urea breakdown in the intestines is accordingly minimized.
Prior art treatment of hepatic failure, such as is characterized by hyperammonemia and portal-systemic encephalopathy, is generally based on attempts to reduce the production of ammonia in the intestines and to restrict dietary protein. Antibiotics are usually applied to prevent urea breakdown. And so, according to prior teachings, the use of keto-acids to alleviate heptatic failure would have been considered ineffective due to the belief that a source of nitrogen for amination of the keto-acids would not be available. Prior art teachings also would not indicate that conversion of the keto-acid analogs of methionine and phenylalanine to amino acids would occur in muscle, as is taught by the present invention. However, since blood from the intestines does not go directly to the liver in this condition but rather to the systemic circulation where, presumably according to prior teachings, amination would not have occurred. The present teachings show that urea breakdown is not necessary to amination of keto-acids in body tissue, that such amination occurs in muscle tissue, and that the total effect of the amination process is the reduction of the accumulation of urea precursors in the body. Individuals suffering from the aforementioned disorders are known to be deficient in protein; in order to provide a useful treatment, as indicated in the co-pending application Ser. No. 669,589 of even date herewith, the compositions employing the keto analogs of the present invention provide for the reduction of ammonia in the bloodstream while simultaneously promoting protein synthesis.
Protein depletion may be treated by introduction of adequate protein to the diet. In instances, either economic or otherwise, where such a course proves impractical, the compositions of the present invention may be used to reduce protein requirements by diverting nitrogen precursors in the body away from urea formation (urea is excreted, resulting in bodily nitrogen loss) by combination of these precursors with keto-acid analogs of essential amino acids to form the amino acids.
It is now also known that the body's mechanisms for conserving protein can be altered, thereby enabling the body to more efficiently conserve endogenous essential amino acids. Keto-acids are thus useful not only as a nitrogen-free "source" of amino acids, but are also useful for diminishing losses of nitrogen from the body due to malnutrition, cancer, chronic infection, diabetes, surgery, trauma, or any other wasting disease or condition which causes wastage of body tissues. Treatment of these conditions in prior practice has involved the introduction into the body of amino acids through a central venous catheter, a dangerous and technically difficult invasive technique, in order to restore a positive nitrogen balance. According to the present invention, a positive nitrogen balance can be accomplished by oral or parenteral venous administration of keto-acids which reduces nitrogen wastage from the body.